Medications for the treatment of RA include disease modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), and the TNF inhibitor etanercept. Multiple new biologic agents currently in development. As the number and expense of treatments increase, clinicians need information to guide treatment in individual RA patients. TNF plays an important role in the pathogenesis of RA and its gene lies in the MHC region near HLA DRB1 (for which alleles containing the shared epitope [SE] have established roles in RA). Thus, genetic variants in the MHC region are logical candidate pharmacogenetic markers. Most previous studies analyzing association between MHC markers and treatment response have been limited by lack of standardized DMARD and corticosteroid regimens, suboptimal outcome measures, short periods of observation, retrospective design, or lack of statistical power due to small numbers of patients. Our preliminary analysis of 457 subjects in the Immunex Early Rheumatoid Arthritis Trial comparing. MTX and etanercept indicates that response is predicted by haplotypes comprising HLA DRB1 alleles and TNF/LTA single nucleotide polymorphisms (SNPs). Neither the SE nor TNF/LTA SNPs account for this finding alone, so it is not clear which area of the MHC influences treatment response. The 1,000 Kb region between HLA DRB1 and TNF/LTA is gene-dense, with many non-HLA immune-related genes that may influence treatment response in RA through as yet undefined mechanisms. The TEAR (Treatment of Early Aggressive RA) trial is a unique, double-blind, multicenter, investigator-initiated, pharmaceutically-sponsored study to compare the efficacy of 2 years of treatment with MTX, triple DMARDs (MTX + SSZ + HCQ), and MTX plus etanercept in 750 subjects. TEAR represents a special and unique opportunity to analyze genetic markers of response in early RA in a rigorous, adequately powered, prospective clinical trial. We believe that these analyses will ultimately lead to information useful in guiding treatment decisions of clinicians caring for patients with RA, which is becoming increasingly important as the number and cost of therapies for RA continue to increase.